Two forms of beta lactam resistance appeared among pathogenic streptococci: penicillin tolerance (reported to occur among clinical isolates of group A and B streptococci, from recurrent infections, Str. sanguis, Str. bovis and Str. faecium) and intrinsic beta lactam resistance (as seen in the multiply drug-resistant South African pneumococci. Four types of studies are planned: 1) The nature of penicillin tolerance (i.e., the relatively weak irreversible effects of penicillin in these bacteria) will be fully characterized along the lines that lead to the first description of penicillin tolerance in our laboratory as the typical response of autolysin-defective pneumococci to penicillin treatment (see nature (1970) 227: 138). Attempts will also be made to test the contribution of tolerance to the invasiveness of Str. sanguis in heart valve infection of rabbits. 2) Biochemical, genetic and morphological studies are planned to understand the mechanism of the rapid bactericidal effect of penicillins in group A streptococci, which show no signs of cell structural defect during antibiotic treatment. 3) Exploratory studies will be done to test if the massive secretion of bacterial surface polymers (recently observed to occur during penicillin treatment of streptococci; Horne and Tomasz, 1977, Antimicrob. Ag. Chemotherap. 11:888.) might not affect the interaction of the bacterial pathogen with host factors, such as the humoral and cellular immune system; and ability of the bacteria to attach to epithelial surfaces. Using DNA from the multiply drug resistant South African pneumococcus, a series of oxacyllin-resistant pneumococcal strains have been constructed in our lab, using the technique of genetic transformation. These isogenic strains offer an excellent opportunity to identify the mechanism of intrinsic lactam resistance in terms of possible changes in the penicillin binding proteins in these resistant bacteria.